Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma: Efficacy, safety, and hepatocyte growth factor and O6-methylguanine-DNA methyltransferase biomarker analyses

Timothy Cloughesy, Gaetano Finocchiaro, Cristóbal Belda-Iniesta, Lawrence Recht, Alba A. Brandes, Estela Pineda, Tom Mikkelsen, Olivier L. Chinot, Carmen Balana, David R. Macdonald, Manfred Westphal, Kirsten Hopkins, Michael Weller, Carlos Bais, Thomas Sandmann, Jean Marie Bruey, Hartmut Koeppen, Bo Liu, Wendy Verret, See Chun PhanDavid S. Shames

Research output: Contribution to journalArticle

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Abstract

Purpose: Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods: At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O6-methylguanine-DNA methyltransferase promoter methylation, and glioblastoma subtype. Results: Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O6-methylguanine-DNA methyltransferase may benefit from Ona + Bev. Conclusion: There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.

Original languageEnglish
Pages (from-to)343-351
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number3
DOIs
Publication statusPublished - Jan 20 2017

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Hepatocyte Growth Factor
Methyltransferases
Glioblastoma
Biomarkers
Placebos
Safety
DNA
Epithelial-Mesenchymal Transition
Disease-Free Survival
Survival
Bevacizumab
O-(6)-methylguanine
onartuzumab
Methylation
Disease Progression
Ligands
Recurrence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma : Efficacy, safety, and hepatocyte growth factor and O6-methylguanine-DNA methyltransferase biomarker analyses. / Cloughesy, Timothy; Finocchiaro, Gaetano; Belda-Iniesta, Cristóbal; Recht, Lawrence; Brandes, Alba A.; Pineda, Estela; Mikkelsen, Tom; Chinot, Olivier L.; Balana, Carmen; Macdonald, David R.; Westphal, Manfred; Hopkins, Kirsten; Weller, Michael; Bais, Carlos; Sandmann, Thomas; Bruey, Jean Marie; Koeppen, Hartmut; Liu, Bo; Verret, Wendy; Phan, See Chun; Shames, David S.

In: Journal of Clinical Oncology, Vol. 35, No. 3, 20.01.2017, p. 343-351.

Research output: Contribution to journalArticle

Cloughesy, T, Finocchiaro, G, Belda-Iniesta, C, Recht, L, Brandes, AA, Pineda, E, Mikkelsen, T, Chinot, OL, Balana, C, Macdonald, DR, Westphal, M, Hopkins, K, Weller, M, Bais, C, Sandmann, T, Bruey, JM, Koeppen, H, Liu, B, Verret, W, Phan, SC & Shames, DS 2017, 'Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma: Efficacy, safety, and hepatocyte growth factor and O6-methylguanine-DNA methyltransferase biomarker analyses', Journal of Clinical Oncology, vol. 35, no. 3, pp. 343-351. https://doi.org/10.1200/JCO.2015.64.7685
Cloughesy, Timothy ; Finocchiaro, Gaetano ; Belda-Iniesta, Cristóbal ; Recht, Lawrence ; Brandes, Alba A. ; Pineda, Estela ; Mikkelsen, Tom ; Chinot, Olivier L. ; Balana, Carmen ; Macdonald, David R. ; Westphal, Manfred ; Hopkins, Kirsten ; Weller, Michael ; Bais, Carlos ; Sandmann, Thomas ; Bruey, Jean Marie ; Koeppen, Hartmut ; Liu, Bo ; Verret, Wendy ; Phan, See Chun ; Shames, David S. / Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma : Efficacy, safety, and hepatocyte growth factor and O6-methylguanine-DNA methyltransferase biomarker analyses. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 3. pp. 343-351.
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abstract = "Purpose: Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods: At first recurrence after chemoradiation, bevacizumab-na{\"i}ve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O6-methylguanine-DNA methyltransferase promoter methylation, and glioblastoma subtype. Results: Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95{\%} CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95{\%} CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5{\%} of patients who received Ona + Bev and 35.9{\%} of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O6-methylguanine-DNA methyltransferase may benefit from Ona + Bev. Conclusion: There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.",
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T1 - Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma

T2 - Efficacy, safety, and hepatocyte growth factor and O6-methylguanine-DNA methyltransferase biomarker analyses

AU - Cloughesy, Timothy

AU - Finocchiaro, Gaetano

AU - Belda-Iniesta, Cristóbal

AU - Recht, Lawrence

AU - Brandes, Alba A.

AU - Pineda, Estela

AU - Mikkelsen, Tom

AU - Chinot, Olivier L.

AU - Balana, Carmen

AU - Macdonald, David R.

AU - Westphal, Manfred

AU - Hopkins, Kirsten

AU - Weller, Michael

AU - Bais, Carlos

AU - Sandmann, Thomas

AU - Bruey, Jean Marie

AU - Koeppen, Hartmut

AU - Liu, Bo

AU - Verret, Wendy

AU - Phan, See Chun

AU - Shames, David S.

PY - 2017/1/20

Y1 - 2017/1/20

N2 - Purpose: Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods: At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O6-methylguanine-DNA methyltransferase promoter methylation, and glioblastoma subtype. Results: Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O6-methylguanine-DNA methyltransferase may benefit from Ona + Bev. Conclusion: There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.

AB - Purpose: Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods: At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O6-methylguanine-DNA methyltransferase promoter methylation, and glioblastoma subtype. Results: Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade ≥ 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O6-methylguanine-DNA methyltransferase may benefit from Ona + Bev. Conclusion: There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.

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